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guanine base of one strand and the fi rst guanine base of the other strand), adopt
distinct conformations. G4 is stacked on top of an adjacent G-quartet and is part of
the fi rst loop. G12 is orientated away from the core of G-quartets and is stacked on
the T7 base. The cation-dependent folding of the d[(G
4
T
4
G
3
)
2
] quadruplex structure
is distinct from that observed for related sequences. While both d[(G
4
T
4
G
4
)
2
] and
d[(G
3
T
4
G
3
)
2
] form bimolecular, diagonally looped G-quadruplex structures in the
presence of Na
+
and K
+
, we have observed this folding to be favoured for d[(G
4
T
4
G
3
)
2
]
in the presence of Na
+
. The structure of d[(G
4
T
4
G
3
)
2
] exhibits a ' slipped - loop '
element. The missing guanine residue at the 3
- end of d(G
4
T
4
G
4
), in terms of the
primary structure, is compensated by slipping of the residues, which thus take its
position within the 3D structure. Such a slipped strand apparently contributes to a
thermodynamic stability of the structure.
An NMR study on the folding of d(G
3
T
4
G
4
), a sequence with the 5
′
terminal
dG residue missing from the d(G
4
T
4
G
4
) sequence, established an unprecedented
topology of a bimolecular G-quadruplex (Figure 3.6b).
244
The structure consists of
three G-quartets. The conformation of guanosine bases is
anti
-
syn
-
syn
-
anti
around
one of the G-quartets, and
syn
-
anti
-
anti
-
anti
in the other two. Two guanine residues,
G3 and G11, are involved in G-quartet formation. Three of the strands are in paral-
lel, while one is in the antiparallel orientation. This type of topology resembles topo-
logical characteristics of (3 + 1) G-quadruplexes of the human telomere repeat
sequences (see above). The outer G-quartets are spanned by diagonal as well as edge-
type loops. Another unusual structural feature of d[(G
3
T
4
G
4
)
2
] is a leap between G19
and G20 over the middle G-quartet and chain reversal between G19 and G20 resi-
dues (Figure 3.6b). The examination of the infl uence of different monovalent cations
on the folding of d(G
3
T
4
G
4
) showed that it forms a bimolecular G-quadruplex with
the same general fold in the presence of K
+
, Na
+
and ammonium ions.
245
′
3.6 Coordination of Cations within d[( TG
4
T )
4
]
Early studies on guanosine gels established a strong correlation between the melting
temperature and the ionic radii of cations, which was an indication of site-specifi c
ion binding by G-quartets.
149
The strong interaction between cations and G-quartets
originates from electrostatic interactions involving the guanine O6 oxygen atoms.
On the other hand, electrostatic repulsions between cations within a G-quadruplex
are substantial. Thus, the exact locations and coordination geometries of cations
within a given G-quadruplex are the result of a balance between attractive inter-
actions with carbonyl oxygen atoms and mutual cation repulsion. Cation coordina-
tion is not restricted to a particular geometry within a G-quadruplex (Figure 3.7).
A series of stacked G-quartets produces a regular geometry, and potential cation
coordination sites, with four O6 atoms within the plane of a G-quartet, or with
eight O6 atoms between two stacked G-quartets. Ions such as K
+
and
15
NH
4
+
(ionic radii 1.33 Å and 1.43 Å, respectively) are too large to coordinate in the
plane of a G-quartet, whereas Na
+
(ionic radius 0.95 Å) is small enough to be
coordinated within the plane of a G-quartet. Thus, as schematically illustrated in
